Two major, underexplored aspects of genetic expression are the specification of cell architecture and the regulation of expression by changes in architecture. These fundamental phenomona underlie differentiated tissue formation and, most importantly, a breakdown in cytoskeleton organization and its regulation function appears to be a universal, and probably obligatory, concomitant of cancer. We have developed two techniques which together constitute a powerful, new approach to cell biology. These are: (1)\embedment-free electron microscopy using both whole mounts and newly developed resin-free sections. Our published work shows that the conventional EM thin section masks more than 95% of cell structure which can be seen with great clarity when the embedding plastic is removed. However, the cytostructure is obscured by soluble proteins and chromatin and the full power of this technique is realized only when combined with (2)\chemical dissection that, while preserving the native morphology of cytostructure, first removes soluble proteins to reveal the cytoskeleton and can then peel away the skeleton and chromatin to display the nuclear matrix. Both the complex networks of the cytoskeleton and the very existence of the nuclear matrix have been hidden by conventional EM. Also, the structural fractions obtained are biochemically well-defined and the protein compositions of the cytoskeleton, chromatin, and nuclear matrix can be determined for the first time. We have found that the major changes during differentiation and in malignant transformation are found, surprisingly, in the nuclear matrix. We have found the cytoarchitecture perturbed by tumor promoters and complete carcinogens in a characteristic way. The morphological signature of these compounds has led us to propose an extremely sensitive, yet rapid and inexpensive screen for promoters and carcinogens that is a major improvement over the Ames test. Oncogenes, introduced with transforming virus, give a similar signature but no other agents do. The regulation of cell metabolism by cell shape is perturbed or destroyed by these agents and a major breakdown in cell function by malignant transformation may have been uncovered. (F)